Most currently available antidepressant drugs rapidly alter neurotransmission in the brain yet require chronic administration to affect mood. These observations suggest that slow biological processes downstream of drug- induced changes in neurotransmission, which are thought to include changes in gene transcription, are likely to be required for the behavioral response to these antidepressant drugs. The goal of this proposal is to advance understanding of the basic brain mechanisms that regulate behavioral responses to chronic antidepressant treatment. We have discovered that the methyl-DNA binding chromatin regulatory protein MeCP2 is a target of regulation by antidepressants, and that mutations in MeCP2 alter behavioral responses to chronic antidepressant treatment in mice. Specifically we find that administration of drugs that enhance serotonin and dopamine neurotransmission in the CNS, including the antidepressant citalopram, induces phosphorylation of MeCP2 at Ser421 (pMeCP2) in selected CNS neurons. To test the functional relevance of pMeCP2 for depressive-like behaviors and antidepressant responses we obtained a strain of mice that bear a germline Ser421Ala mutation knocked into the Mecp2 gene that renders MeCP2 protein nonphosphorylatable at this site. We have tested the consequence of this mutation on depressive-like behaviors and response to chronic antidepressant treatment in these mice in the social defeat stress paradigm. We find that both MeCP2 knockin mice and their wildtype littermates show similar levels of social avoidance following defeat. However whereas chronic imipramine treatment rescues social interaction in the wildtype mice, this drug treatment fails to ameliorate social avoidance in the knockin mice. On the basis of these and other preliminary data we hypothesize that phosphorylation of MeCP2 at Ser421 is required for at least a subset of behavioral responses to chronic antidepressant treatment. This is a completely novel hypothesis. No prior studies have examined a role for MeCP2 in depressive-like behaviors or response to antidepressant treatment. Our findings could have a substantial impact on the understanding of brain processes that underlie depressive-like behaviors and response to antidepressants by linking this important epigenetic regulator of chromatin to the actions of chronic antidepressant administration on the brain. We propose to address our hypothesis with the following two specific aims: 1) To analyze depressive-like behaviors and antidepressant responses in MeCP2 KI mice and 2) To identify neural circuits that underlie MeCP2-dependent effects on depressive-like behaviors. PUBLIC HEALTH RELEVANCE: Depression and related mood disorders affect millions of Americans and cost our society tens of billions of dollars each year in medical treatments, lost productivity, and premature mortality. This proposal will address the role of the epigenetic transcriptional regulator MeCP2 in the chronic actions of antidepressant drugs. This study has the potential to reveal novel insights into the underlying brain mechanisms that regulate depressive- like behaviors and response to antidepressant treatment.